tbuckley/cabot-search huggingface dataset:
Abstract 5048: Imaging based EGFR mutation subtype classification using EfficientNet
Authors: Daniel L. Franklin, Tara Pattilachan, Anthony Magliocco
Journal: Cancer Research (2022)

Abstract This study aimed to determine whether EfficientNet-B0 was able to classify EGFR mutation subtypes with H&amp;E stained whole slide images of lung and lymph node tissue. Background: Non-small cell lung cancer (NSCLC) accounts for the majority of all lung adenocarcinomas, with estimates that up to a third of such cases have a mutation in their epidermal growth factor receptor (EGFR). EGFR mutations can occur in various subtypes, such as Exon19 deletion, and L858R substitution, which are important for early therapy decisions. Here, we propose a deep learning approach for detecting and classifying EGFR mutation subtypes, which will greatly reduce the cost of determining mutation status, allowing for testing in a low resource setting. Methods: An EfficientNet-B0 model was trained with whole slide images of lung tissue or metastatic lymph nodes with known EGFR mutation subtype (wild type, exon19 deletion or L858R substitution). Regions of interest were tiled into 512x512 pixel images. The RGB .jpeg tiles are augmented by rotating 90°, 180°, 270°, and mirroring. The model was initialized with random parameters and trained with a batch size of 32, a learning rate of 0.0001 for 1 epoch before the validation loss increased for the next 5 epochs. Results: The model achieved a slide AUC of 0.8333, and a tile AUC of 0.8010. Slide AUC is the result of averaging all tiles within a slide and measuring performance based on correctly predicted slides (n=18). Tile AUC is the result of measuring performance based on correctly predicted tiles (n=102,000). Conclusion: Using EfficientNet-B0 architecture as the basis for our EGFR mutation classification system, we were able to create a top performing model and achieve a slide AUC of 0.833 and tile AUC of 0.801. Healthcare providers and researchers may utilize this AI model in clinical settings to allow for detection of EGFR mutation from routinely captured images and bypass expensive and time consuming sequencing methods. Table 1. Number of image tiles used and the number of slides they were extracted from. Train Validation Test Exon19 tiles 187,384 47,904 33,096 L858R tiles 166,288 19,512 26,136 Wild type tiles 225,944 27,696 42,768 Exon19 slides 47 6 6 L858R slides 46 6 6 WIld type slides 43 6 6 Citation Format: Daniel L. Franklin, Tara Pattilachan, Anthony Magliocco. Imaging based EGFR mutation subtype classification using EfficientNet [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5048.
Abstract 661: Androgen deprivation therapy allows for effective anti-TIGIT immunotherapy in murine model of castration resistant prostate cancer
Authors: Fanny Polesso, Xiangnan Guan, Zheng Xia, Amy E. Moran
Journal: Cancer Research (2022)

Abstract Prostate cancer is the second leading cause of cancer associated mortality in men, and for reasons that remain unclear, immunotherapy treatments have largely failed in patients with advanced prostate cancer. Standard of care therapy for these patients relies on androgen deprivation therapies (ADT) to block testosterone production combined with small molecules that inhibit androgen synthesis and/or the function of the androgen receptor (AR). Importantly, androgens are reported to be immunosuppressive; therefore, we postulated that androgen axis blockade might promote response to immunotherapy. In the recent years, the co-inhibitory receptor TIGIT has emerged as a promising immunotherapy target, and we observed that TIGIT is highly expressed on tumor infiltrating T cells and NK cells in metastatic castration resistant prostate cancer (CRPC) patients treated with the AR antagonist enzalutamide. Likewise, in a mouse model of CRPC, we show that tumor infiltrating T cells express TIGIT and that treatment with enzalutamide increases its expression. In this model, neither treatment with anti-TIGIT alone nor with chemical castration and enzalutamide affects tumor growth. Remarkably, the combination of anti-TIGIT with chemical castration and enzalutamide leads to delayed tumor growth and long-term cures in about 60% of the animals. Taken together, our data suggest that androgen receptor blockade sensitizes immune cells in the tumor to respond to anti-TIGIT immunotherapy. Citation Format: Fanny Polesso, Xiangnan Guan, Zheng Xia, Amy E. Moran. Androgen deprivation therapy allows for effective anti-TIGIT immunotherapy in murine model of castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 661.
Abstract 1557: Defining the regulatory effects of candidate oncogenic non-coding RNA LINC00473 in fibrolamellar carcinoma
Authors: Rosanna K. Ma, Matt Kanke, Khashayar Vakili, Praveen Sethupathy
Journal: Cancer Research (2022)

Abstract Fibrolamellar carcinoma (FLC) is a rare form of liver cancer that disproportionately affects adolescents, usually presents at advanced stages with no known risk factors or serum biomarkers, and exhibits high intrinsic drug resistance. The signature genetic event of FLC was identified in 2014 as a ~400kb heterozygous deletion resulting in the DNAJB1-PRKACA (or DP) fusion oncogene. The DP fusion occurs in over 80% of FLC patients and is sufficient for tumorigenesis in mice. Targeting DP pharmacologically has proved challenging; therefore, we performed multiple genome-scale studies to identify and target candidate downstream effectors that drive FLC development and progression. LINC00473, a primate-specific long non-coding RNA (lncRNA), emerged as a top candidate oncogene. Multiple models reveal strong induction of LINC00473 in FLC, including: (1) primary tumor relative to normal liver; (2) FLC patient-derived xenograft tumors (PDX); and (3) a newly developed FLC cell line derived from the PDX. Importantly, LINC00473 is upregulated in response to the fusion oncogene in HEK293 cells that express DP via CRISPR/Cas9-mediated deletion, and is dramatically downregulated in FLC cells upon DP knockdown by three independent siRNAs (collaboration with Alnylam Pharmaceuticals, Inc). Stable in vitro suppression of LINC00473 using two distinct short hairpin RNAs results in RNA depletion and significant reduction of cell proliferation. Concordantly, the stable overexpression of LINC00473 in FLC cells leads to a robust increase in gene expression and elevated cell proliferation. These data suggest that LINC00473 is a key regulator of FLC cell growth and survival. Next, to investigate the regulatory effects of LINC00473, we first determined that the lncRNA is enriched in the nucleus of FLC cells using subcellular fractionation followed by qRT-PCR, suggesting a role in transcriptional regulation. To investigate if LINC00473 acts downstream of the DP fusion to regulate gene expression programs mediating FLC phenotypes, we performed RNA-seq on FLC cells that harbor stable LINC00473 knockdown or overexpression. These data enabled us to define the altered gene expression profiles that result from LINC00473 dysregulation. Overall, this study elucidates the functional role of LINC00473 in the progression of FLC and helps advance the field by providing important biological insights into this disease. Citation Format: Rosanna K. Ma, Matt Kanke, Khashayar Vakili, Praveen Sethupathy. Defining the regulatory effects of candidate oncogenic non-coding RNA LINC00473 in fibrolamellar carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1557.
Abstract 6123: High-fat diets promote lung metastasis of breast cancer by activating lung fibroblasts
Authors: Huiping Chen, Penghan Huang, Jianing Chen, Erwei Song
Journal: Cancer Research (2022)

Abstract Metastasis is the main cause of patient death among many tumor types including breast cancer and breast cancer patients with obesity have higher risk of distant metastases during 10-year follow-up. Diet is one of the main and manageable factors that cause obesity and regular intake of high-fat diets can induce obesity. In addition, fibroblasts, as the most abundant stromal cell type in tumor microenvironment, are involved in cancer metastasis. However, the role of fibroblasts and the downstream mechanism in metastasis of patients with high-fat diet remains unclear. In this study, we fed MMTV-PyMT transgenic mice with high-fat diet to obtain a high-fat tumorigenesis model, and isolate primary lung fibroblasts and then coculture them with breast cancer cells to explore the interaction. We found that a high-fat diet can significantly promote progression of primary breast cancer and lung metastasis, and that before weight difference shows, there is a different chemotactic influence of lung fibroblasts on breast cancer cell between high-fat diet and normal diet group. And we observed increased chemotactic function of primary lung fibroblasts in high-fat diet group. Moreover, tumor cells treated with primary lung fibroblasts in high-fat diet group show increased ability of adhesion, suggesting that high-fat diet chemoattracts breast cancer cell colonization by activating lung fibroblasts. Collectively, we explored the functional differences of lung fibroblast and the key factors for the lung colonization of recruited breast cancer cells. Our findings suggest that dietary patterns are associated with the risk of breast cancer metastasis and targeting activated fibroblasts in pre-metastatic microenvironment may serve as potential early therapeutic strategy to reduce breast cancer lung metastasis. Citation Format: Huiping Chen, Penghan Huang, Jianing Chen, Erwei Song. High-fat diets promote lung metastasis of breast cancer by activating lung fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6123.
Abstract 5769: Comprehensive analysis of genomic alteration in histologic components of myxoid liposarcoma
Authors: Jee Hoon Chae, Sun il Kim, Do Hee Kim, Sangkyum Kim, Junjeong Choi
Journal: Cancer Research (2022)

Abstract Purpose: Myxoid liposarcoma (MLS) is the most common type of liposarcoma in humans. Tumor with round cell component shows poor clinical prognosis. Currently, specific target therapies for this tumor type have not been developed. We performed next-generation sequencing (NGS) analysis of paired samples to investigate genomic alteration in MLS with two histologic features. Methods: Whole exome sequencing (WES) and transcriptome sequencing data were acquired from formalin-fixed paraffin-embedded samples of 10 patients. We performed differential gene expression analysis and pathway analysis between the conventional myxoid liposarcoma area lesion and that of round cell component using transcriptome sequencing data. In addition, we analyzed characteristics of mutational signatures in the two histologic features of MLS using WES data. Results: CD37 showed the most significant expression in round cell components of myxoid liposarcoma (RMLS) compared to conventional MLS. The immune response pathway was significantly enriched in the conventional lesion. The pathway involving cell mitotic and metabolic processes were represented considerably in with RMLS. FUS-DDIT3/EWSR1-DDIT3 fusion oncogene was detected in these RMLS samples more frequently than MLS. Some patients showed mutational signatures related to oxidative stress. Conclusion: The expression of CD37 was highly expressed in almost all the RMLS. We identified smoking profile signature characteristics in these two samples, but no significant mutational difference was placed between the RMLS and MLS samples. In RMLS, the fusion oncogene and other overexpression oncogenes that occur in the cell cycle affect lipid metabolism due to oxidative stress such as ROS. Finally, we observed CD37 expression by performing IHC only in RMLS samples. The above data suggest that CD37 and other markers can be a promising biomarker target in myxoid liposarcoma with unfavorable histological features. Citation Format: Jee Hoon Chae, Sun il Kim, Do Hee Kim, Sangkyum Kim, Junjeong Choi. Comprehensive analysis of genomic alteration in histologic components of myxoid liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5769.
Abstract 2670: ERAS-601, a potent allosteric inhibitor of SHP2, synergistically enhances the efficacy of sotorasib/adagrasib and cetuximab in NSCLC, CRC, and HNSCC tumor models
Authors: Leenus Martin, Roopal Patel, Jingchuan Zhang, Robin Nevarez, Taylor Congdon, Les Brail, Robert Shoemaker
Journal: Cancer Research (2022)

Abstract ERAS-601 is a potent, small molecule allosteric inhibitor of wildtype SHP2, a non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene. ERAS-601 inhibits wild type SHP2 biochemically with an IC50 of 4.6 nM and demonstrates selectivity across panels of 300 kinases and 12 phosphatases. SHP2 mediates upstream receptor tyrosine kinase (RTK) signaling via its phosphatase-mediated regulation of guanine nucleotide exchange factors (GEFs). ERAS-601 inhibits the SHP2 dependent cycling of KRAS from the inactive GDP-bound state to the active GTP-bound state and demonstrates anti-proliferative activity in KRASG12C and EGFR amplified cell lines. The combination of upstream blockade of RAS-GTP cycling by ERAS-601 with inhibition of KRASG12C by a selective KRASG12C inhibitor synergistically inhibits cellular proliferation in multiple KRASG12C mutated human cancer cell lines. The combinations of ERAS-601 with KRASG12C inhibitors achieve tumor growth inhibition that is superior to the respective ERAS-601 and KRASG12C monotherapies in NSCLC and CRC CDX and PDX tumor models. Similarly, the combination of ERAS-601 with an EGFR antibody, cetuximab, inhibits oncogenic RAS/MAPK signaling as measured by pERK1/2 and enhances the anti-proliferative activity of cetuximab in RAS/RAF wild type CRC and HPV-negative HNSCC cell lines. The combination of ERAS-601 with cetuximab achieves tumor growth inhibition that is superior to respective ERAS-601 and cetuximab monotherapies in RAS/RAF wild type CRC and HPV-negative HNSCC CDX and PDX tumor models. These nonclinical data support the clinical development of ERAS-601 in combination with a KRASG12C inhibitor in NSCLC and CRC tumors, and ERAS-601 in combination with cetuximab in RAS/RAF wild type CRC as well as HPV-negative HNSCC tumors. Both combinations are being studied in ongoing clinical studies (HERKULES-2, NCT04959981; FLAGSHP-1, NCT04670679). Citation Format: Leenus Martin, Roopal Patel, Jingchuan Zhang, Robin Nevarez, Taylor Congdon, Les Brail, Robert Shoemaker. ERAS-601, a potent allosteric inhibitor of SHP2, synergistically enhances the efficacy of sotorasib/adagrasib and cetuximab in NSCLC, CRC, and HNSCC tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2670.
Abstract 1563: Spatial transcriptomics reveals heterogeneity and pathway dependencies of cancer associated fibroblasts in pancreatic ductal adenocarcinoma
Authors: Giuseppina Caligiuri, Jennifer Thalappillil, Juliene Hinds, Elise T. Courtois, William F. Flynn, Paul Robson, Alexander Dobin, Youngkyu Park, David A. Tuveson
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDA) is a deadly disease characterized by an immunosuppressive microenvironment and a dense stroma that encapsulates the tumor, making therapeutic targeting particularly challenging. One of the main cellular components of PDA tumor microenvironment (TME) is cancer associated fibroblasts (CAFs), whose function is to sustain tumor growth and provide structural support to the TME. Previously, we established the existence of three transcriptional subtypes of CAFs, myCAF, iCAF and apCAF, each with distinct functions and location in respect to cancer cells. Two of these subtypes, myCAF and iCAF, display a highly plastic potential in vitro and can transdifferentiate into one another upon activation of specific signaling pathways. The plasticity observed supports the existence of transitional CAF sub-states that have previously eluded observation due to technical limitations to their isolation. Through a combination of spatial transcriptomics and fluorescent in situ hybridization (FISH) on tumor samples obtained from KPC (KrasLSL-G12D; p53LSL-R172H; PDX-CRE) and FPC (KrasFrt-LSL-G12V-Frt; p53LSL-R172H; PDX-CRE; Rosa26FlpOERT2) mice, two PDA mouse models displaying a Kras G12D and G12V mutation respectively, we were able to confirm the presence of the previously identified CAF subtypes and two additional CAF sub-states. These sub-states are associated with the expression of specific markers and display different pathway enrichment. Notably, Kras G12D and G12V mutations generate similar organization of the stroma and heterogeneity of the CAF population. Subsequently, to understand the contribution of activating Kras mutation to these CAF phenotypes, we utilized the unique feature of the FPC mouse model which allows the excision of Kras G12V once the tumor has fully developed. Through FISH analysis, we observed deep reorganization of the stroma and a shift in marker expressions within the CAF populations upon Kras excision. Overall, the data here presented offers insight into the diversity of PDA CAFs and the role of mutated Kras in regulating CAF subtypes and stromal organization. Citation Format: Giuseppina Caligiuri, Jennifer Thalappillil, Juliene Hinds, Elise T. Courtois, William F. Flynn, Paul Robson, Alexander Dobin, Youngkyu Park, David A. Tuveson. Spatial transcriptomics reveals heterogeneity and pathway dependencies of cancer associated fibroblasts in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1563.
Abstract 4062: Activity of 3 Bromopyruvate in human tumor primary culture 3-dimensional explants using ex vivo analysis of programmed cell death
Authors: Adam Jeremiah Nagourney, Paulo D'Amora, Steven Scott Evans, Paula Bernard, Federico Francisco, Young Ko, Thomas Stockwell, Maxine Johnson, Robert Alan Nagourney
Journal: Cancer Research (2022)

Abstract Altered metabolism is a hallmark of human malignancy. The “Warburg Effect “reflecting increased glycolytic activity in the presence of oxygen represents an opportunity to target specific features of cancer to induce selective toxicity to malignantly transformed cells. 3-bromopyruvate (3-BP) is a pyruvate analogue that inhibits hexokinase II at the mitochondrial level resulting in cancer cell death. Numerous studies have confirmed activity for 3-BP in human SW480 and HT 29 colon carcinoma, glioblastoma (U373MG), HTP-1 leukemic and other cell lines. Our interest in exploring the activity of 3-BP in human tumor primary culture explants led to the application of the ex vivo analysis of programmed cell death in 19 patient tumors. The intent was to develop concertation ranges for future studies and explore disease-specific activity. Methods: Fresh Sterile tumor samples were mechanically and enzymatically disaggregated and 3-dimensional organoids of desired size isolated by density centrifugation. Blood samples were isolated by density centrifugation. Cell suspensions in modified RPMI media were exposed to serial dilutions of 3-BP for 72 hours and then assessed for cell death by morphology, staining characteristics and ATP content by luciferase. Viability was scored against saline-exposed controls, normalized to 100%. Results: 3BP reveals activity in human tumor explants. Activity varied by cancer type. Hematologic tumors including NHL, CLL and AML were found sensitive as were several solid tumors including GI and lung cancers. Of interest lower degrees of activity were observed in breast and ovarian cancers that are generally considered chemo-sensitive . Activity in 2 fibrolamellar cancers could suggest a novel therapy for this drug refractory neoplasm. Studies are underway examining 3-BP correlations with other classes of drugs and metabolic inhibitors as well as 3-BP combinatorial potential. Supported by the Fibro fighters Foundation Citation Format: Adam Jeremiah Nagourney, Paulo D'Amora, Steven Scott Evans, Paula Bernard, Federico Francisco, Young Ko, Thomas Stockwell, Maxine Johnson, Robert Alan Nagourney. Activity of 3 Bromopyruvate in human tumor primary culture 3-dimensional explants using ex vivo analysis of programmed cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4062.